Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis.

Thuong, Nguyen T T, Heemskerk, Dorothee, Tram, Trinh T B, Thao, Le T P, Ramakrishnan, Lalita, Ha, Vu T N, Bang, Nguyen D, Chau, Tran T H, Lan, Nguyen H, Caws, Maxine ORCID: https://orcid.org/0000-0002-9109-350X, Dunstan, Sarah J, Chau, Nguyen V V, Wolbers, Marcel, Mai, Nguyen T H and Thwaites, Guy E (2017) 'Leukotriene A4 Hydrolase Genotype and HIV Infection Influence Intracerebral Inflammation and Survival From Tuberculous Meningitis.'. Journal of Infectious Disease, Vol 215, Issue 7, pp. 1020-1028.

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Abstract

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis, yet very little is known about the pathophysiology. We hypothesized that the genotype of leukotriene A4 hydrolase (encoded by LTA4H), which determines inflammatory eicosanoid expression, influences intracerebral inflammation, and predicts survival from TBM. We characterized the pretreatment clinical and intracerebral inflammatory phenotype and 9-month survival of 764 adults with TBM. All were genotyped for single-nucleotide polymorphism rs17525495, and inflammatory phenotype was defined by cerebrospinal fluid (CSF) leukocyte and cytokine concentrations. LTA4H genotype predicted survival of human immunodeficiency virus (HIV)-uninfected patients, with TT-genotype patients significantly more likely to survive TBM than CC-genotype patients, according to Cox regression analysis (univariate P = .040 and multivariable P = .037). HIV-uninfected, TT-genotype patients had high CSF proinflammatory cytokine concentrations, with intermediate and lower concentrations in those with CT and CC genotypes. Increased CSF cytokine concentrations correlated with more-severe disease, but patients with low CSF leukocytes and cytokine concentrations were more likely to die from TBM. HIV infection independently predicted death due to TBM (hazard ratio, 3.94; 95% confidence interval, 2.79-5.56) and was associated with globally increased CSF cytokine concentrations, independent of LTA4H genotype. LTA4H genotype and HIV infection influence pretreatment inflammatory phenotype and survival from TBM. LTA4H genotype may predict adjunctive corticosteroid responsiveness in HIV-uninfected individuals.

Item Type:	Article
Subjects:	QU Biochemistry > Enzymes > QU 136 Hydrolases QU Biochemistry > Genetics > QU 500 Genetic phenomena QW Microbiology and Immunology > Immunity by Type > QW 568 Cellular immunity. Immunologic cytotoxicity. Immunocompetence. Immunologic factors (General) WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General) WL Nervous System > WL 200 Meninges. Blood-brain barrier
Faculty: Department:	Clinical Sciences & International Health > Clinical Sciences Department Clinical Sciences & International Health > International Public Health Department
Digital Object Identifer (DOI):	https://doi.org/10.1093/infdis/jix050
SWORD Depositor:	JISC Pubrouter
Depositing User:	JISC Pubrouter
Date Deposited:	10 May 2017 10:21
Last Modified:	07 Dec 2018 10:33
URI:	https://archive.lstmed.ac.uk/id/eprint/7062

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